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Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

ABSTRACT: The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3? and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3? signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.

SUBMITTER: Chakraborty A

PROVIDER: S-EPMC3052691 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

Chakraborty Anutosh A Koldobskiy Michael A MA Bello Nicholas T NT Maxwell Micah M Potter James J JJ Juluri Krishna R KR Maag David D Kim Seyun S Huang Alex S AS Dailey Megan J MJ Saleh Masoumeh M Snowman Adele M AM Moran Timothy H TH Mezey Esteban E Snyder Solomon H SH

Cell 20101201 6

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3β and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3β signaling reduced in skeletal muscle, white adipose tissue, an ...[more]

PMID: 21145457

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Project description:BackgroundVascular endothelial dysfunction is an essential part of the pathophysiology of type 2 diabetes and its complications. In type 2 diabetes, endothelial dysfunction is characterized by reduced insulin signaling and increased transendothelial transport of fatty acids (FA). As the Abl kinase inhibitor imatinib was previously shown to reverse type 2 diabetes and to inhibit VEGF signaling via Abl kinases, we studied the effect of imatinib on vascular insulin sensitivity and fatty acid transport in vivo and in vitro.MethodsC57/BL6J mice were fed a chow diet or Western diet (WD), and received daily imatinib injections for two weeks. Insulin-mediated vasoreactivity of resistance arteries was studied using intravital microscopy, and metabolic insulin sensitivity using the hyperinsulinemic-euglycemic clamp. The effect of imatinib on triglyceride content in skeletal muscle and heart in vivo was also determined. In vitro, the effect of imatinib on fatty acid transport was studied in human umbilical vein endothelial cells (HUVECs) by evaluating the effect of imatinib on fluorescently labeled FA uptake both under basal and VEGF-B-stimulated conditions.ResultsImatinib prevented the WD-induced weight gain in mice, independently from food intake. In line with this, imatinib enhanced insulin-mediated vasoreactivity of resistance arteries in the WD-fed mice. However, imatinib did not affect triglyceride content in muscle. In cultured endothelial cells, VEGF-B stimulation resulted in a time-dependent uptake of fatty acids in parallel with increased phosphorylation of the Abl kinase substrate Crk-like protein (CrkL) at Tyr207. Although imatinib effectively prevented VEGF-B-mediated Abl kinase activation, it had no effect on VEGF-B mediated endothelial FA uptake.ConclusionImatinib prevents weight gain and preserves insulin-mediated vasodilation in WD-fed mice, but does not affect endothelial FA transport despite inhibiting VEGF-B signaling. The beneficial effect of imatinib on insulin-mediated vasodilation may contribute to the anti-diabetic effects of imatinib.

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Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

Publications

Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain.

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